Human Gene Module / Chromosome 19 / MAST3

MAST3microtubule associated serine/threonine kinase 3

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
15 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
19p13.11
Associated Disorders
-
Relevance to Autism

De novo missense variants in the MAST3 gene have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the MSSNG cohort (Yuen et al., 2017). Shu et al., 2021 reported 11 individuals with de novo missense variants in the STK domain of the MAST3 gene presenting with developmental and epileptic encephalopathy (DEE) ; six of these patients also presented with ASD or autistic features, while a seventh patient also presented with stereotypy. Subsequent functional analysis of MAST3 missense variants in this report demonstrated variable but generally lower expression with concomitant increased phosphorylation of the MAST3 target ARPP-16 compared to wild-type, suggesting gain-of-function effects. Shu et al., 2022 reported four additional individuals with de novo MAST3 missense variants; two of these patients were diagnosed with ASD by ABC and CARS. Additional analysis of published large-scale exome sequencing data in this report demonstrated an excess of missense variants in the DUF domain of MAST3 in ASD cohorts, as well as an excess of missense variants in the STK domain in DEE cohorts, when compared with gnomAD.

Molecular Function

Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in cytoskeleton organization; intracellular signal transduction; and peptidyl-serine phosphorylation. MAST3 has been shown to interact with the ASD-associated gene PTEN (Valiente et al., 2005).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MAST3 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Valiente M , et al. (2005) No -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support - Iwama K et al. (2019) No -
5 Primary - Spinelli E et al. (2021) No ASD or autistic features, ADHD, stereotypy
6 Recent Recommendation - Shu L et al. (2022) No ASD, epilepsy/seizures
7 Support - Zhou X et al. (2022) Yes -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2961G>A p.Glu987%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1217G>C p.Arg406Pro missense_variant De novo - - 34185323 Spinelli E et al. (2021)
c.1528G>A p.Gly510Ser missense_variant De novo - - 34185323 Spinelli E et al. (2021)
c.1543G>A p.Gly515Ser missense_variant De novo - - 34185323 Spinelli E et al. (2021)
c.1543G>A p.Gly515Ser missense_variant Unknown - - 34185323 Spinelli E et al. (2021)
c.1547T>C p.Leu516Pro missense_variant De Novo - - 34185323 Spinelli E et al. (2021)
c.1651G>T p.Val551Leu missense_variant De novo - - 34185323 Spinelli E et al. (2021)
c.140C>T p.Ser47Phe missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.302C>T p.Ser101Phe missense_variant De novo - Simplex 35095415 Shu L et al. (2022)
c.311C>T p.Ser104Leu missense_variant De novo - Simplex 35095415 Shu L et al. (2022)
c.1543G>A p.Gly515Ser missense_variant De novo - Simplex 35095415 Shu L et al. (2022)
c.1547T>C p.Leu516Pro missense_variant De novo - Simplex 35095415 Shu L et al. (2022)
c.288C>G p.Thr96%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.835C>T p.Pro279Ser missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1963T>C p.Phe655Leu missense_variant De novo - Multiplex 34185323 Spinelli E et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Interaction with PTEN

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
3

Increased from to 3

Description

Interaction with PTEN

Krishnan Probability Score

Score 0.44723474347466

Ranking 13640/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99892526061784

Ranking 1084/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.82596692815052

Ranking 2748/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.46611866161032

Ranking 778/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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